Hyaluronic acid based copolymers

ABSTRACT

Hyaluronic acid (HA) conjugates or crosslinked HAs compositions for coating an implantable device are provided. The implantable device can be used for treating a disorder such as atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/631,399 filed on Sep. 28, 2012 which is a divisional applicationof U.S. application Ser. No. 10/835,912 entitled “Hyaluronic Acid BasedCopolymers” filed on Apr. 30, 2004 and issued as U.S. Pat. No.8,293,890, the teachings of which are incorporated by reference hereinin its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a hyaluronic acid copolymer andcompositions formed therefrom for coating an implantable medical device.

2. Description of the Background

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels, such as by employing a stent. Stentsact as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically stents arecapable of being compressed, so that they can be inserted through smalllumens via catheters, and then expanded to a larger diameter once theyare at the desired location.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site.Local delivery of a therapeutic substance is a preferred method oftreatment because the substance is concentrated at a specific site andthus smaller total levels of medication can be administered incomparison to systemic dosages that often produce adverse or even toxicside effects for the patient. One method of medicating a stent involvesthe use of a polymeric carrier coated onto the surface of the stent.

Despite their utility, stents have been plagued by two problems, namely,acute occlusion due to thrombosis and persistent occurrence ofrestenosis. Recent studies show that coronary stenting results insignificant platelet, polymorphonuclear leukocyte, and macrophageactivation, as well as activation of the coagulation pathway whichinduce clots despite passivation and/or anti-coagulation treatment ofthe stent surface. This limitation relates to the surface exposure ofadhesion receptors on activated platelets to the foreign surface of thestent, producing the aforementioned thrombogenic activity that must becountered with intense anti-coagulation regimens. Subacute stentthrombosis occurs most frequently during the first few days afterimplantation and almost always in the first two weeks. Thereafter,neointimal cells including proliferating smooth muscle cells from thevessel wall and endothelial hyperplastic cells encompass the stentsurface and ameliorate the risk of stent thrombosis.

Hyaluronic acid (HA) has been used as a material for impartingbiobeneficial properties to stent coatings (see, for example, U.S. Pat.No. 5,849,368) that help reduce restenosis and thrombosis. However, HAis very hydrophilic and highly water soluble and organic solventinsoluble. Also, because of its high water solubility, HA lacksfilm-forming ability on an implantable device such as a stent. It isalso to be note that HA molecule is delicate, that degradation of themolecule can lead to a dramatic decrease in molecular weight.

The compositions and the coatings formed thereof disclosed hereinaddress the above described problems and other needs.

SUMMARY OF THE INVENTION

Provided herein are hyaluronic acid (HA) conjugates including HAcopolymers and crosslinked HAs and compositions formed therefrom forcoating implantable devices such as a stent that can be a metallic stentor a polymeric stent which can be durable, biodegradable orbioabsorbable. The HA conjugate can have molecular HA and at least acomponent that can be heparin, poly(ethylene glycol) (PEG), hydrophobicside chains, biocompatible hydrophobic polymers, and combinationsthereof. Alternatively, the HA conjugate can have a moiety derived fromHA or HA derivative and at least one moiety or derivative derived fromheparin, poly(ethylene glycol) (PEG), hydrophobic side chains,biocompatible hydrophobic polymers, and combinations thereof.

The HA conjugates can be formed by functionalizing HA with a reactiveagent that would provide the functionalized HA a reactive and accessiblereactive group and reacting the functionalized HA with hydrophobicspecies, PEG, heparin, biocompatible polymers, and combinations thereof.Representative reactive agents include hydrazide, dihydrazide,aziridine, epoxides, and vinyl sulphones.

In one embodiment, crosslinked HAs can be formed by crosslinkingfunctionalized HAs bearing crosslinking moieties in the presence ofbiocompatible initiator by applying a crosslinking means such asheating, UV, or combinations thereof. Crosslinking moieties such asacryloyl or methacryloyl moieties can be introduced into HA by theirreaction with functionalized HA such as HA-hydrazide.

In another embodiment, crosslinked HA can be formed by reacting HA witha biocompatible crosslinker such as the aziridine crosslinker fromSybron Chemicals (New Jersey) and other crosslinkers having two or morelinking moieties.

In still another embodiment, hydrophobic species, poly(ethylene glycol)(PEG), or heparin can be functionalized with two or more crosslinkingmoieties such as hydrazides, aziridines, epoxides, vinyl sulfphones,aldehydes and used as crosslinker to crosslink HA.

In a further embodiment, the cyclic dimmer 3-hydroxypropionatealdehyde(3-HPA) can be used as a crosslinker to crosslink HA.

The HA conjugate or crosslinked HA can be used to form a coating on animplantable device, which may include a bioactive agent. Representativebioactive agents include, but are not limited to, ABT-578™, paclitaxel,docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat,mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugsthereof, co-drugs thereof, and combinations thereof.

The composition provided herein can be coated onto an implantabledevice. The implantable device can be any implantable device. In oneembodiment, the implantable device is a drug-delivery stent. Theimplantable device can be used for the treatment of a medical conditionsuch as atherosclerosis, thrombosis, restenosis, high cholesterol,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic structure of hyaluronic acid's building blocks;FIG. 1B shows the structure of adipic dihydrazide.

DETAILED DESCRIPTION

Provided herein are hyaluronic acid (HA) conjugates including HAcopolymers and crosslinked HAs and compositions formed therefrom forcoating implantable devices such as a stent that can be a metallic stentor a polymeric stent which can be durable, biodegradable orbioabsorbable. The HA conjugate can have molecular HA and at least acomponent that can be heparin, poly(ethylene glycol) (PEG), hydrophobicside chains, biocompatible hydrophobic polymers, and combinationsthereof. Alternatively, the HA conjugate can have a moiety derived fromHA or HA derivative and at least one moiety or derivative derived fromheparin, poly(ethylene glycol) (PEG), hydrophobic side chains,biocompatible hydrophobic polymers, and combinations thereof. The HAcontaining conjugate can have organic solvent solubility and filmforming property. The coating including the HA conjugate has acute andlong term biobeneficial properties. In addition, the coating can providefor controlled release of a bioactive agent such as everolimus.

As used herein, biobeneficial properties of a material refers to thematerial capable of enhancing the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent. Anti-fouling is defined as preventing,delaying or reducing the amount of formation of protein build-up causedby the body's reaction to foreign material. Similarly, non-thrombogenicand anti-inflammatory means completely preventing, delaying orminimizing to a desirable degree the formation of thrombin andinflammation.

The term HA conjugate as used herein refers to a substance that includesa HA component that can be HA or a moiety derived from HA and at leastone other component that can be a species or a polymer as definedherein. The components in the HA conjugate can have an interaction suchas covalent bonding, ionic interaction, hydrogen bonding, van der Waalsinteraction, and interpenetrating network.

Modification of HA

The conjugate can be formed from a functionalized HA with a modifyingspecies such as hydrophobic side chain species, a hydrophobic,biodegradable polymers, poly(ethylene glycol) (PEG), or heparin. Theconjugate can also be formed from a HA with a functionalized modifyingspecies.

A. Functionalization of HA

The HA backbone has two potential sites for functionalization, namely, acarboxylic acid and a primary hydroxyl (FIG. 1A). HA can reach molecularweights in the millions of Daltons, while its repeating unit has amolecular weight of 435 Daltons. This results in the HA molecule havinga very large number of potential reactive sites, which allows one tofunctionalize HA via a linking agent for modification of HA.

In one embodiment, the linking agent can be a difunctional reactivespecies having two reactive groups. One of the two reactive groups linksto Site 1 or Site 2 of HA (FIG. 1A), and the other reactive group linksto another polymer or material to form a modified HA such as a blockcopolymer comprising the HA. For example, the difunctional reactivespecies can be a dihydrazide. The dihydrazide can be any dihydrazide. Asan example, the dihydrazide can be adipic dihydrazide (FIG. 1B).Functionalization of HA can be achieved by coupling of adipicdihydrazide with HA in the presence of an agent such as carbodiimide(ethyl carbodiimide (EDCI), for example) (see, Luo, Y., et al., J.Contr. Release 69:169-184 (2000)) (Scheme 1).

The reaction can be carried out in water. In order to avoid crosslinkingof HA by the dihydrazide, the reaction can be carried out in an excessof dihydrazide, and the degree of functionalization can be controlled bythe amount of carbodiimide used. For example, using a stoichiometricamount of carbodiimide would result in about 100% functionalization ofHA, and using 50% of the stoichiometric amount of carbodiimide wouldresult in about 50% functionalization of HA. The amount of carbodiimideused can range from about 0% to about 100% stoichiometric amount, fromabout 20% to about 80% stoichiometric amount, or from about 30% to about50% stoichiometric amount.

In another embodiment, HA can be functionalized via an aziridine, whichcan be conducted in water (see, for example, Gianolino, D. A., et al.,Crosslinked sodium hyaluronate containing labile linkages, Abstract fromSociety for Biomaterials 2002). For example, HA can be functionalized bycoupling with pentaerythritol tris(3-aziridinopropionate), which iscommercially available, in water (scheme 2).

In a further embodiment, the functionalization of HA can be carried outby any other suitable agents. Exemplary other suitable agents includeepoxides and/or vinyl sulphones. The functionalized HA then can becoupled with another polymer or material to form a derivatized HA underconditions known in the art suitable for coupling.

The functionalized HA can bear hydrazide group, terminal amine group,terminal anhydride group, terminal aldehyde group, and combinationsthereof.

B. Conjugation with Hydrophobic Species

In accordance with one embodiment of the present invention,functionalized HA can be coupled with a hydrophobic species to form aconjugate with hydrophobic side chains. Exemplary useful hydrophobicspecies to provide for the hydrophobic side chains of the conjugateinclude, for example, saturated and unsaturated fatty acids, saturatedand unsaturated fatty alcohols. Exemplary useful hydrophobic, saturatedand unsaturated fatty acids include, for example, castor oil, laurate,stearate, palmitate and/or oleate. Exemplary saturated and unsaturatedfatty alcohols include, for example, hexanol, dodecanol, stanol, sterol,cholesterol, and/or cetyl. In some embodiments, the hydrophobic speciesis a short chain hydrophobic species. As used herein, the term “shortchain hydrophobic species” refers to a C2-C20 hydrophobic species.

In some embodiments, a hydrophobic compound can be conjugated to HA suchthat the compound has a Hildebrand solubility parameter (δ) less than 12(cal/cm³)^(1/2), less than 11 (cal/cm³)^(1/2), less than 10.5(cal/cm³)^(1/2), or alternatively less than 9 (cal/cm³)^(1/2.)

In accordance with another embodiment of the present invention, thefunctionalized HA can be coupled with a biocompatible hydrophobicpolymer, which can be non-absorbable, biodegradable or bioabsorbable.Useful biocompatible hydrophobic polymers include, for example,poly(ester amide), poly(ester amide) that may contain alkyl groups,amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethyleneglycol (PEG), polyhydroxyalkanoates (PHA), poly(2-hydroxyalkanoates),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalknaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers comprising any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, polyesters, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide), polycaprolactone,poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(phosphoesters),polyphosphazenes, poly(amino acids), polysaccharides, collagen,chitosan, alginate, polyethers, polyamides, polyurethanes,polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropyleneoxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP),alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA),alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOHor EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™ (poly (vinylidenefluoride-co-hexafluoropropene) and combinations thereof.

The hydrophobic side chain species and biodegradable polymers can besimply added in excess and coupled via a carbodiimide in an appropriatesolvent that is a common solvent for the functionalized HA and thehydrophobic side chain species or biodegradable polymer. For example,HA-hydrizide can be coupled to high molecular weight polylactic acidwith 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) in an acetonesolution with an adjusted pH for example pH=8.

While the conjugate can be formed from a functionalized HA and thehydrophobic side chain species or hydrophobic biodegradable polymers, asdescribed above, the conjugate also can be formed from anunfunctionalized HA and a functionalized hydrophobic side chain speciesor hydrophobic biodegradable polymer. For example, HA can form aconjugate with commercially available octanoic hydrazide by directcoupling of the HA and octanoic hydrazide in a solvent that is a solventfor both materials.

C. Conjugation with Poly(ethylene glycol)

In accordance with a further aspect of the present invention,functionalized HA can form a conjugate with a high molecular weight PEG.The PEG useful for forming the HA-PEG conjugates described herein has amolecular weight in the range between 500 Daltons to 250,000 Daltons,specifically between 1,000 Daltons and 100,000 Dalton, and morespecifically between 5,000 Daltons and 50,000 Daltons.

In one embodiment, PEG can be functionalized so as to form a PEG bearinga terminal aldehyde. The PEG with a terminal aldehyde can readily reactat room temperature in water with a hydrazide functionalized HA to forma HA-PEG conjugate.

In another embodiment, PEG can be functionalized so as to form a PEGbearing a terminal amine group. The PEG bearing a terminal amine groupcan react directly with HA that was functionalized with a terminalanhydride, yielding a block copolymer, HA-co-PEG.

In a further embodiment, PEG can be functionalized so as to form a PEGsuccinamide. The PEG succinamide then can be coupled to HA to from aconjugate comprising HA and PEG.

PEG functionalized with amino, aldehyde, or succinyl, or combinationsthereof are commercially available. For example, linear amino-PEG ofaverage molecular weight of 6,000 Daltons can be purchased fromShearwater Polymers, Inc. (Huntsville, Ala.).

In still a further embodiment, PEG can be modified to bear an aminegroup, and HA can be oxidized by an oxidizing agent such as a peroxideor nitrous acid to have terminal aldehyde groups. The amine terminatedPEG can then be coupled to the HA bearing terminal aldehyde groups viareductive amination to form a HA and PEG conjugate.

D. Conjugation with Heparin

In accordance with another aspect of the present invention, HA can forma conjugate with heparin. The conjugation can be achieved by coupling afunctionalized HA with an unfunctionalized heparin, a functionalizedheparin with an unfunctionalized HA, or a functionalized heparin with afunctionalized heparin.

In one embodiment, an aldehyde terminated HA can be coupled toamino-functionalized heparin, which is commercially available, viareductive amination to form a HA/heparin conjugate.

In another embodiment, HA can be derivatized with sebacic dihydrazide asdescribed above, PEG-dialdehyde, or a bis-succinimidyl moiety. An amineterminated heparin can then be allowed to react with the derivatized HAto form HA/heparin conjugates having sebacicdihydrazide, PEG, andbis-succinimidyl linkages, respectively.

As used herein, the term “heparin” includes molecular heparin and any ofheparin derivatives. Heparin derivatives can be any functional orstructural variation of heparin. Representative variations includealkali metal or alkaline—earth metal salts of heparin, such as sodiumheparin (e.g., hepsal or pularin), potassium heparin (e.g., clarin),lithium heparin, calcium heparin (e.g., calciparine), magnesium heparin(e.g., cutheparine), and low molecular weight heparin (e.g., ardeparinsodium). Other examples include heparin sulfate, heparinoids, heparinbased compounds and heparin having a hydrophobic counter-ion.

The HA conjugates described herein can take a variety of formulae. Inone embodiment, the conjugate can be HA-co-PEG or HA-co-heparin, whichis end-capped with hydrophobic species such as fatty acids such asstearate, laurate, palmitate, and oleate, fatty alcohols such ashexanol, dodecanol, stanol, sterol, cholesterol, and cetyl, orbiodegradable hydrophobic polymers such as poly(ester amide) that mayoptionally contain alkyl, amino acid, PEG or alcohol groups,polycaprolactone, polylactide, polyglycolide, polyhydroxyalkanoate(PHA), polydioxanone (PDS), or PHA-PEG. The PHA may includepoly(α-hydroxyacids), poly(β-hydroxyacid) such aspoly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate)(PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate)(PHH), or poly(4-hydroxyacid) such as poly (4-hydroxybutyrate),poly(4-hydroxyvalerate) or poly(4-hydroxyhexanoate). The hydrophobicspecies or biodegradable hydrophobic polymers can be side chainsattached to HA-co-PEG or HA-co-heparin.

In one embodiment, the HA conjugate is a PEG-HA-(C12-C18 alkyl)conjugate.

E. Crosslinking of Functionalized HA

In accordance with a further embodiment of the present invention, amodified HA can be crosslinked using a crosslinker. Because of the highhydrophilicity of HA, modified HAs may become a weak hydrogel whenimmersed in water. Crosslinking of the modified HA would lead to theformation of a coating comprising the modified HA.

In one embodiment, acrylic moieties can be introduced into a modified HAby reacting a HA-hydrazide with acryloyl or methacryloyl chloride toform a HA bearing olefinic moieties such as acryloyl or methacryloylgroups. This material can be mixed with a biocompatible initiator,applied to an implantable device by, for example, dip coating, and thencrosslinked upon exposure to a radiation, for example, UV radiation.

In another embodiment, an un-functionalized HA and a crosslinking agentwith multiple aziridine groups can be separately applied to the surfaceof an implantable device to coat and left to react at a temperature suchas an ambient temperature. The crosslinking agent can be, for example,pentaerythritol tris(3-aziridinopropionate) available from SybronChemicals (NJ). Any other agents having multiple aziridine groups canalso be employed.

In a further embodiment of the present invention, a hydrophobic sidechain species described herein or a polymer such as PEG can befunctionalized with two or more hydrazides, aziridines, aldehydes,amines, diacrylate, bisacrylamide, and other functionalities for use ascrosslinkers. A functionalized or un-functionalized HA can be subjectedto crosslink with these crosslinkers with or without heating. An exampleof a hydrophobic side chain species is cyclic dimmer3-hydroxypropionatealdehyde (3-HPA) found in reuterin.

In still a further embodiment, HA can be coupled to a polymeric surfaceon an implantable device via, for example, plasma treatment. The surfacecan be first treated with an argon (Ar) and NH₃ plasma to attach aminefunctionalities that can then be reacted with an anhydride, for example,succinic anhydride, to the surface. These functionalities can then becoupled to one or more functionalized HA, e.g., HA-hydrazide in thepresence of a carbodiimide to form a crosslinked HA surface. Ifdesirable, the crosslinked HA surface can be further modified with abiobeneficial material such as heparin. The biobeneficial material canbe functionalized with one or more crosslinking moieties such ashydrazide or aziridine groups, with or without a PEG spacer, andattached to the crosslinked HA surface after dip coating.

Bioactive Agent

The modified HA described herein can be used to form coatingcompositions that may include one or more bioactive agents. Thebioactive agent can be any agent which is biologically active, forexample, a therapeutic, prophylactic, or diagnostic agent. Examples ofsuitable therapeutic and prophylactic agents include synthetic inorganicand organic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Nucleic acidsequences include genes, antisense molecules which bind to complementaryDNA to inhibit transcription, and ribozymes. Compounds with a wide rangeof molecular weight, for example, between about 100 and about 500,000grams or more per mole or between about 100 and about 500,000 grams ormore per mole, can be encapsulated. Some other examples of suitablematerials include proteins such as antibodies, receptor ligands, andenzymes, peptides such as adhesion peptides, and saccharides andpolysaccharides. Some further examples of materials which can beincluded include blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator; antigensfor immunization; hormones and growth factors; polysaccharides such asheparin; oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. Representativediagnostic agents are agents detectable by x-ray, fluorescence, magneticresonance imaging, radioactivity, ultrasound, computer tomagraphy (CT)and positron emission tomagraphy (PET).

In the case of controlled release, a wide range of different bioactiveagents can be incorporated into a controlled release device. Theseinclude hydrophobic, hydrophilic, and high molecular weightmacromolecules such as proteins. The bioactive compound can beincorporated into polymeric coating in a percent loading of between0.01% and 70% by weight, more preferably between 5% and 50% by weight.

In one embodiment, the bioactive agent can be for inhibiting theactivity of vascular smooth muscle cells. More specifically, thebioactive agent can be aimed at inhibiting abnormal or inappropriatemigration and/or proliferation of smooth muscle cells for the inhibitionof restenosis. The bioactive agent can also include any substancecapable of exerting a therapeutic or prophylactic effect for thepatient. For example, the bioactive agent can be for enhancing woundhealing in a vascular site or improving the structural and elasticproperties of the vascular site. Examples of active agents includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck).Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The bioactive agentcan also fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitricoxide or nitric oxide donors, super oxide dismutases, super oxidedismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), sirolimus and sirolimus derivatives, paclitaxel andpaclitaxel derivatives, estradiol, steroidal anti-inflammatory agents,antibiotics, anticancer agents, dietary supplements such as variousvitamins, and a combination thereof. An example of an antiallergic agentis permirolast potassium. Other therapeutic substances or agents whichmay be appropriate include alpha-interferon, genetically engineeredepithelial cells, ABT-578™, paclitaxel, docetaxel, paclitaxelderivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid,estradiol, clobetasol, dexamethasone, rapamycin,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugsthereof, co-drugs thereof, and combinations thereof.

The foregoing substances are listed by way of example and are not meantto be limiting. Other active agents which are currently available orthat may be developed in the future are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent required to inhibit the desired cellular activityof the vascular region can depend upon factors such as the particularcircumstances of the patient; the nature of the trauma; the nature ofthe therapy desired; the time over which the ingredient administeredresides at the vascular site; and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Coatings on Implantable Devices

Compositions having any of the HA conjugates and/or crosslinked HAs canbe used to coat implantable devices, with or without a bioactive agent.The coating described herein can be formed as a single layer of coatingon an implantable device or in conjunction with, such as on top of,another layer of coating including a polymer other than the HA conjugateor crosslinked HA described herein. In some embodiments, the HA coatingcould be the outmost layer of a coated device. In other embodiments, theHA layer could be a top coat layer for a polymer-drug reservoir layer ora polymer free drug layer.

The HA conjugate or crosslinked HA can also be blended with one or morepolymers such as biocompatible and/or bioabsorbable polymers. Examplesinclude, but not limited to, poly(ester amide), poly(ester amide) thatmay optionally contain alkyl groups, amino acid groups, or poly(ethyleneglycol) (PEG) groups, polyethylene glycol (PEG), polyhydroxyalkanoates(PHA), poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalknaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymerscomprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, polyesters, poly(D,L-lactide),poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide),polycaprolactone, poly(D,L-lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(phosphoesters), polyphosphazenes, poly(amino acids),polysaccharides, collagen, chitosan, alginate, polyethers, polyamides,polyurethanes, polyalkylenes, polyalkylene oxides, polyethylene oxide,polypropylene oxide, polyethylene glycol (PEG), PHA-PEG,polyvinylpyrrolidone (PVP), alkylene vinyl acetate copolymers such asethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such asethylene vinyl alcohol (EVOH or EVAL), poly(n-butyl methacrylate) (PBMA)and combinations thereof. In one preferred embodiment, the blend is withSOLEF™ (poly (vinylidene fluoride-co-hexafluoropropene).

In another embodiment, the composition described herein can be used forcoating an implantable device such as a drug-delivery stent forcontrolled release of a bioactive agent. The composition may compriseany of HA conjugates or crosslinked HAs alone or as a blend componentwith other biocompatible polymers.

In some further embodiments, with the chemistries mentioned previouslydifferent type of networks and architectures can be achieved. Exemplarysuch architectures can be, for example, physical crosslinking orinterpenetrating networks. In one embodiment, an interpenetratingnetwork (IPN) can be made by locking HA in a tightly crosslinked networkof PEG diacrylate. In this IPN, the HA is not covalently bound to thecrosslinked polymer, but trapped in the network. HA can also bephysically locked in the coating by being applied simultaneously with anultra high molecular weight polymer such as poly(D,L-lactide). Inaddition, HA can be covalently bound to a thermoreversible gel based ona N-isopropylacrylamide (NIPAM)-PEG diblock copolymer.

Method of Coating a Device

The composition described herein can be coated on an implantable devicesuch as a stent by spray coating or any other coating process availablein the art. Generally, the coating involves dissolving or suspending thecomposition, or one or more components thereof, in a solvent or solventmixture to form a solution, suspension, or dispersion of the compositionor one or more components thereof, applying the solution or suspensionto an implantable device, and removing the solvent or solvent mixture toform a coating or a layer of coating. Suspensions or dispersions of thecomposition described herein can be in the form of latex or emulsion ofmicroparticles having a size between 1 nanometer and 100 microns,preferably between 1 nanometer and 10 microns. Heat and/or pressuretreatment can be applied to any of the steps involved herein. Inaddition, if desirable, the coating described here can be subjected tofurther heat and/or pressure treatment. Some additional exemplaryprocesses of coating an implantable device that may be used to form acoating on an implantable using the composition described herein aredescribed in, for example, Lambert T L, et al. Circulation, 1994; 90:1003-1011; Hwang C W, et al. Circulation, 2001; 104: 600-605; Van derGiessen W J, et al. Circulation, 1996; 94: 1690-1697; Lincoff A M, etal. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, J AmericanCollege Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster 1174-15;Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. ZKardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation 2003,107: 4, 559-64.

The composition can be coated onto the implantable device in the form ofa single layer of coating or components of the composition can be coatedonto the device in the form of separate layers of coating.

The bioactive agent can be coated onto an implantable device as aseparate layer or together with the composition having any of the HAconjugates or crosslinked HAs. In one embodiment, the bioactive agent iscoated onto the device as a separate layer. In another embodiment, thebioactive agent is coated onto the device together with the compositiondescribed herein.

In a further embodiment, the bioactive agent or a second bioactive agentcan be loaded onto a coating described here by swell-loading. Thecomposition having one or more of HA conjugates and/or functionalizedHAs can be formulated with a crosslinker such as hydrazides, aziridines,aldehydes, amines, diacrylate, bisacrylamide and applied on top of amedical device coating. Upon photoactivated or thermally initiatedcrosslinking, a thin surface gel comprising the one or more of the HAconjugates or crosslinked HAs described herein would form. The bioactiveagent described herein and/or a second drug can then be swell-loaded inthis surface gel. The swell loaded bioactive agent can have a fastrelease rate, e.g., about 50% to 100% release in vivo in a period of,for example, from about one, two, or three hours to about one day or twodays. This would allow the forming of a medical device coating systemthat has a bimodal release rate that may be efficacious for morerefractory lesions such as diabetes, long vessel, high cholesterol, orvulnerable plaques by forming a coating with a first agent that has acontrolled release of the first agent and a surface gel described hereinwith a second agent swell loaded therein. The first agent and the secondagent can be the same agent or different agents, which are describedabove.

As used herein, the term “solvent” refers to a liquid substance orcomposition that is compatible with the polymer and/or the drug iscapable of dissolving or suspending the drug and/or polymericcomposition or one or more components thereof at a desiredconcentration. Representative examples of solvents include chloroform,acetone, water (buffered saline), dimethylsulfoxide (DMSO), propyleneglycol monomethyl ether (PM,) iso-propylalcohol (IPA), n-propyl alcohol,methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF),dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane,cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate,butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetonealcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylenechloride, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane,chlorobenzene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethylphosphoramide and a combination thereof.

Examples of medical devices that can be used with the chemicals of thepresent invention include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts), artificial heartvalves, cerebrospinal fluid shunts, pacemaker electrodes, andendocardial leads (e.g., FINELINE and ENDOTAK, available from GuidantCorporation, Santa Clara, Calif.). The underlying structure of thedevice can be of virtually any design. The device can be made of ametallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316E), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In one embodiment, the implantabledevice is a metallic stent or a biodegradable or bioabsorbable stent.

The compositions described herein can be coated onto a bare metallic orpolymeric implantable device or on top of a drug eluting or drugdelivery systems.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will be retained on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, thrombosis, and restenosis. Stents may be placed ina wide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

The implantable device comprising a coating described herein can be usedto treat an animal having a condition or disorder that requires atreatment. Such an animal can be treated by, for example, implanting adevice described herein in the animal. Preferably, the animal is a humanbeing. Exemplary disorders or conditions that can be treated by themethod disclosed herein include, but not limited to, atherosclerosis,thrombosis, restenosis, high cholesterol, hemorrhage, vasculardissection or perforation, vascular aneurysm, vulnerable plaque, chronictotal occlusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, and combinations thereof.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples. All parameters and data are not to beconstrued to unduly limit the scope of the embodiments of the invention.

Example 1

A stent can be coated according to the procedure and in theconfiguration as specified below:

Primer layer: 100 μg of PLA;

Matrix drug layer: 500 μg of poly(lactic acid) (PLA) and everolimus(weight ratio of PLA to everolimus can be 1:1, for example); and

Topcoat layer: 300 μg of HA conjugate blended with PLA (weight ratio ofHA conjugate to everolimus can be 1:1, for example).

Example 2

A stent can be coated according to the procedure and in theconfiguration as specified below:

Primer layer: 100 μg of PLA;

Matrix drug layer: 500 μg of PLA and everolimus (weight ratio of PLA toeverolimus can be 1:1, for example); and

Topcoat layer: 300 μg HA conjugate blended with PEGlyated PLA (e.g.triblock PLA-PEG-PLA) (weight ratio of HA conjugate to PEGlyated PLA canbe 1:1, for example)

Example 3

A stent can be coated according to the procedure and in theconfiguration as specified below:

Primer layer: 100 μg of PLA;

Matrix drug layer: 500 μg of PLA and everolimus (weight ratio of PLA toeverolimus can be 1:1, for example); and

Topcoat layer: 300 μg pure HA conjugate.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

ADDITIONAL EMBODIMENTS

1. A hyaluronic acid (HA) conjugate comprising HA and at least acomponent selected from the group consisting of

heparin,

poly(ethylene glycol) (PEG),

hydrophobic side chains,

biocompatible hydrophobic polymers, and

combinations thereof.

2. The HA conjugate of embodiment 1 wherein the short hydrophobic sidechains are selected from the group consisting of saturated andunsaturated fatty acids and fatty alcohols.

3. The HA conjugate of embodiment 1 wherein the biocompatiblehydrophobic polymers are selected from the group consisting ofpoly(ester amide), poly(ester amide) that may contain alkyl groups,amino acid groups, or poly(ethylene glycol) (PEG) groups, polyethyleneglycol (PEG), polyhydroxyalkanoates (PHA), polyesters,poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), polycaprolactone,poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(phosphoesters),polyphosphazenes, poly(amino acids), polysaccharides, collagen,chitosan, alginate, polyethers, polyamides, polyurethanes,polyalkylenes, polyalkylene oxides, polyethylene oxide, polypropyleneoxide, polyethylene glycol (PEG), PHA-PEG, polyvinylpyrrolidone (PVP),alkylene vinyl acetate copolymers such as ethylene vinyl acetate (EVA),alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVOHor EVAL), poly(n-butyl methacrylate) (PBMA), SOLEF™ (poly (vinylidenefluoride-co-hexafluoropropene) and combinations thereof.

4. The HA conjugate of embodiment 3 wherein the PHA is selected from thegroup consisting of poly(2-hydroxyalkanoates),poly(3-hydroxyalkanoates), poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate),poly(3-hydroxyoctanoate), poly(4-hydroxyalkanoate),poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers comprising any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, and combinations thereof.

5. The HA conjugate of embodiment 1 wherein the hydrophobic side chainsare selected from the group consisting of castor oil, laurate, state,palmitate, oleate, hexanol, dodecanol, stanol, sterol, cholesterol,cetyl, and combination thereof.

6. The HA conjugate of embodiment 1 comprising a heparin and acrosslinker which comprises a moiety selected from the group consistingof difunctional carbodiimide, PEG-dialdehyde, and a bis-succinidylmoieties.

7. The HA conjugate of embodiment 1 comprising a poly(ester amide) whichoptionally comprises one or more groups selected from the groupconsisting of alkyl, amino acids, PEG, and combinations thereof.

8. The HA conjugate of embodiment 1 wherein the biocompatible polymer isbiodegradable.

9. The HA conjugate of embodiment 1 which is a copolymer comprising aPEG-HA-(C12-C18 alkyl) conjugate.

10 A crosslinked HA composition produced by a process comprisingcrosslinking a HA having crosslinking groups by a crosslinking meansselected from the group consisting of photo radiation, heating, chemicalreaction, physical crosslinking, and combinations thereof.

11. The crosslinked HA composition of embodiment 10 wherein thecrosslinking groups are olefinic groups, and

wherein the crosslinking means is photo radiation.

12. The crosslinked HA composition of embodiment 11 wherein the olefinicgroups are selected from the group consisting of acryloyl groups,methacryloyl groups, and combinations thereof.

13. A crosslinked HA composition produced by a process comprisingcrosslinking HA with a crosslinker by chemical reaction.

14. The crosslinked HA composition of embodiment 13 wherein thecrosslinker comprises a hydrophobic moiety or PEG and two or morecrosslinking moieties.

15. The crosslinked HA composition of embodiment 14 wherein thehydrophobic moiety is selected from the group consisting of saturatedand unsaturated fatty acids, fatty alcohols, hydrophobic polymers, andcombinations thereof and

wherein the two or more crosslinking moieties are selected from thegroup consisting of hydazides, azeridines, aldehydes, amines,diacrylate, bisacrylamide, and combinations thereof.

16. The crosslinked HA composition of embodiment 14 wherein thehydrophobic moiety is selected from the group consisting of castor oil,laurate, state, palmitate, oleate, hexanol, dodecanol, stanol, sterol,cholesterol, cetyl, poly (ester amides), poly(caprolactone),polylactide, polyglycolide, poly(lactide-co-glycolide),poly(DL-lactide-co-glycolide), polyhydroxyalkanoate (PHA),poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate)(PHBV), poly(3-hydroxyproprionate) (PHP), poly(3-hydroxyhexanoate)(PHH), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate);poly(4-hydroxyhexanoate), poly(dioxanone), and PHA-PEG, and acombination thereof.

17. The crosslinked HA composition of embodiment 15 wherein thecrosslinker is cyclic dimmer of 3-hydroxypropionatealdehyde.

18. An implantable device comprising the HA conjugate of embodiment 1.

19. An implantable device comprising the HA conjugate of embodiment 2.

20. An implantable device comprising the HA conjugate of embodiment 3.

21. An implantable device comprising the HA conjugate of embodiment 4.

22. An implantable device comprising the HA conjugate of embodiment 5.

23. An implantable device comprising the HA conjugate of embodiment 6.

24. An implantable device comprising the HA conjugate of embodiment 7.

25. An implantable device comprising the HA conjugate of embodiment 8.

26. An implantable device comprising the HA conjugate of embodiment 9.

27. An implantable device comprising the crosslinked HA composition ofembodiment 10.

28. An implantable device comprising the crosslinked HA composition ofembodiment 11.

29. An implantable device comprising the crosslinked HA composition ofembodiment 12.

30. An implantable device comprising the crosslinked HA composition ofembodiment 13.

31. An implantable device comprising the crosslinked HA composition ofembodiment 14.

32. An implantable device comprising the crosslinked HA composition ofembodiment 15.

33. An implantable device comprising the crosslinked HA composition ofembodiment 16.

34. An implantable device comprising the crosslinked HA composition ofembodiment 17.

35. The implantable device of embodiment 18 further comprising abioactive agent.

36. The implantable device of embodiment 18 further comprising abioactive agent selected from the group consisting of ABT-578™,paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus,batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone,rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugsthereof, co-drugs thereof, and combinations thereof.

37. The implantable device of embodiment 27 further comprising abioactive agent.

38. The implantable device of embodiment 27 further comprising abioactive agent selected from the group consisting of ABT-578™,paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus,batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone,rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugsthereof, co-drugs thereof, and combinations thereof.

49. A method of treating a disorder selected from the group consistingof atherosclerosis, thrombosis, restenosis, high cholesterol,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, and combinations thereof,comprising:

implanting in the human being the implantable device of embodiment 18.

50. A method of treating a disorder selected from the group consistingof atherosclerosis, thrombosis, restenosis, high cholesterol,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, and combinations thereof,comprising:

implanting in the human being the implantable device of embodiment 27.

51. A hyaluronic acid (HA) conjugate comprising a moiety derived from HAand at least one moiety derived from a material selected from the groupconsisting of

heparin,

poly(ethylene glycol) (PEG),

hydrophobic side chains,

biocompatible hydrophobic polymers, and

combinations thereof.

52. An implantable device comprising the HA conjugate of embodiment 51.

53. The implantable device of embodiment 52 further comprising abioactive agent.

54. A method of treating a disorder selected from the group consistingof atherosclerosis, thrombosis, restenosis, high cholesterol,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, and combinations thereof,comprising:

implanting in the human being the implantable device of embodiment 53.

1. A hyaluronic acid (HA) conjugate comprising a moiety derived from HAand at least one moiety derived from heparin.
 2. (canceled) 3.(canceled)
 4. (canceled)
 5. (canceled)
 6. The HA conjugate of claim 1,wherein the HA conjugate comprises a HA derivatized with a moietyselected from the group consisting of sebacic dihydrazide,PEG-dialdehyde, and a bis-succinidyl moiety.
 7. (canceled)
 8. The HAconjugate of claim 1, wherein the biocompatible polymer isbiodegradable.
 9. An implantable device comprising the HA conjugate ofclaim
 1. 10. The implantable device of claim 9, further comprising abioactive agent.
 11. The implantable device of claim 10, wherein thebioactive agent is selected from the group consisting of ABT-578™,paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus,batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone,rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugsthereof, co-drugs thereof, and combinations thereof.
 12. A method oftreating a disorder selected from the group consisting ofatherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage,vascular dissection or perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, claudication, anastomotic proliferationfor vein and artificial grafts, bile duct obstruction, ureterobstruction, tumor obstruction, and combinations thereof, comprising:implanting in a human being an implantable device comprising the HAconjugate of claim
 1. 13. The HA conjugate of claim 1, wherein theheparin derivative is an alkali metal or alkaline-earth metal salts ofheparin.
 14. The HA conjugate of claim 13, the alkali metal oralkaline-earth metal salts of heparin is selected from the groupconsisting of sodium heparin, potassium heparin, lithium heparin,calcium heparin, magnesium heparin, and low molecular weight heparin.15. The HA conjugate of claim 1, wherein the heparin derivative isselected from the group consisting of heparin sulfate, heparinoids, andheparin having a hydrophobic counter-ion.
 16. The HA conjugate of claim1, wherein the HA conjugate is end-capped with hydrophobic species. 17.The HA conjugate of claim 1, wherein the hydrophobic species is selectedfrom the group consisting of stearate, laurate, palmitate, and oleate,fatty alcohols, and poly(ester amide) that optionally contains alkyl,amino acid, PEG or alcohol groups, polycaprolactone, polylactide,polyglycolide, polyhydroxyalkanoate (PHA), polydioxanone (PDS), orPHA-PEG.
 18. The HA conjugate of claim 17, wherein the fatty alcohol isselected from the group consisting of hexanol, dodecanol, stanol,sterol, cholesterol, and cetyl.
 19. The HA conjugate of claim 17,wherein the PHA may include poly(α-hydroxyacids), poly(β-hydroxyacid)such as poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate)(PHP), poly(3-hydroxyhexanoate) (PHH), poly(4-hydroxyacid), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), orpoly(4-hydroxyhexanoate).